PROJECT SUMMARY Fetal and neonatal development is highly sensitive to maternal environment. Effects of maternal stress, nutrition, and infections on developmental programming are well documented, and we have recently shown that maternal mutations can also impact behavior of genetically normal offspring by altering the fetal, perinatal and/or early postnatal environment. Social behavior, a core dimension of many neurodevelopmental disorders, is programmable by maternal Fmr1 haploinsufficiency. This intergenerational effect is associated with dysregulated activity of the mesolimbic/amygdala regions during social interaction. Specifically, ventral tegmental area, nucleus accumbens, and amygdala activity is linked to social behavior, and the observed dysfunction in these regions raises the possibility of a causal relationship with the observed phenotype. Additionally, we found a maternal FMRP deficiency- associated reduction in dopamine autoreceptor expression and function, as well as an attenuated behavioral response to oxytocin administration. Our data suggest that maternal FMRP may alter life-long dopamine signaling by programming expression of dopamine autoreceptors. Abnormal dopamine signaling has been associated with numerous neurodevelopmental and psychiatric conditions including ADHD, schizophrenia, anxiety, affective disorders and autism, expanding the potential impact of this research beyond Fragile X-related behavioral dysfunction. The aim of the proposed research is to ascertain whether maternal FMRP-dependent changes in sociability are caused by reduced dopamine autoreceptor expression and/or are associated with abnormal oxytonergic modulation of midbrain dopamine signaling. Experiments in Aim 1 will assess a causal link between maternal FMRP deficiency, the differentially expressed dopamine autoreceptor gene, and its effect on sociability. In Aim 2, we will ascertain whether maternal FMRP deficiency-related attenuation of behavioral responsivity to exogenous oxytocin is mediated by altered oxytocin receptor expression or function in the ventral tegmental area and/or nucleus accumbens.